The rheumatoid arthritis (RA) synovial tissue (ST) is an aggressive tissue replete with macrophages, lymphocytes, fibroblasts, and newly formed blood vessels. Monocyte/macrophages and fibroblasts are key producers of a number of cytokines thought to be responsible in large part, for the inflammation and joint destruction found in the RA joint. For instance, we and other have shown that these macrophages are important producers of the proinflammatory cytokines interleukin (IL)-8, monocyte chemoattractant protein-1, and growth related gene productalpha (groalpha). These cytokines act in concert to mediate inflammation, in some cases angiogenesis (see Koch, et al Science, 25 1798, 1992), and the resultant joint destruction. While there are a number of existing therapies for RA, in many patients the disease process still is very severe resulting in joint destruction, debilitation, and deformity. Down regulating cytokine production may help treat the disease process. In this proposal we hope to study gene delivery systems using human and rat synovial cell cultures and a rat adjuvant-induced arthritis model which mimics human RA. The main aims of this proposal are to examine the potential of two related anti- inflammatory cytokines, IL-4 and IL- 13 to down regulate RA inflammation using a gene therapy approach. IL-4 and IL-13 may be useful in RA gene therapy since they are both potent macrophage down relating factors. IL-4 is a potent inhibitor of angiogenesis as well. Moreover, IL-4 has been shown to have a beneficial effect on an animal model of arthritis. In this proposal we will construct adenoviral vectors bearing either the IL-4 or IL-13 genes. We will then examine whether IL-4 and Il-13 genes can be transduced into human ST cells, using adenoviral vectors. We will determine whether a selectable marker gene and the IL-4 and IL-13 genes are expressed. We will then determine whether transduced IL-4 or IL-13 suppress the production of inflammatory cytokines by RA ST cells. Next, we will determine whether we can mitigate both the course of proinflammatory cytokine production and arthritis in a rat adjuvant-induced arthritis model. Additionally, this work will lead to a better understanding of the requirements for gene therapy in RA with other anti- inflammatory genes. We hope that use of gene therapy employing IL-4 or Il-13 genes will result in a promising new therapy for RA, which afflicts many patients each year.